Fluid shear stress from blood flow, sensed by the endothelium, is a major regulatory influence in the vascular system. I will describe two ongoing projects about the role of fluid shear stress in vascular homeostasis and disease. First, our studies of normal vessel homeostasis suggest that endothelial cells have a shear stress set point that determines inward vs. outward remodeling. This set point is different for vascular vs. lymphatic endothelial cells and is determined by levels of VEGF receptors. Second, our studies of atherosclerosis, which occurs at regions of disturbed flow, have shown that changes in the extracellular matrix contributes to the inflammatory remodeling of the vessel wall. I will present our recent work elucidating a mechanism that mediates this connection between matrix remodeling and inflammation.